YUPELRI (revefenacin) inhalation solution

YUPELRI (revefenacin) inhalation solution

YUPELRI (revefenacin) inhalation solution

YUPELRI is a sterile, clear, colorless, aqueous solution of revefenacin. Revefenacin, the active component of YUPELRI, is an anticholinergic. The chemical name for revefenacin is 1-(2-{4-[(4-carbamoylpiperidin-1-yl)methyl]-N-methylbenzamido}ethyl)piperidin-4-yl N-({1,1’-biphenyl}-2-yl)carbamate.

Revefenacin has a molecular weight of 597.76 and its empirical formula is C35H43N5O4.

Revefenacin is a white to off-white crystalline powder and is slightly soluble in water.

YUPELRI is supplied as 3 mL of revefenacin solution packaged in a unit-dose low-density polyethylene vial overwrapped in a foil pouch. Each vial contains 175 mcg of revefenacin in 3 mL of an isotonic, sterile aqueous solution containing citric acid, sodium chloride, sodium citrate, and water for injection at pH 5.0. Hydrochloric acid or sodium hydroxide may be used to adjust the pH.

YUPELRI does not require dilution prior to administration by nebulization. Like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the nebulization system used, and compressor performance.

Using the PARI LC® Sprint nebulizer connected to a PARI Trek® S compressor under in vitro conditions, the mean delivered dose from the mouthpiece was approximately 62 mcg (35% of label claim), at a mean flow rate of 4 LPM. The mean nebulization time was 8 minutes.

YUPELRI should only be administered via a standard jet nebulizer connected to an air compressor with an adequate airflow, and equipped with a mouthpiece.

INDICATIONS AND USAGE

YUPELRI is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

Mechanism of Action

Revefenacin is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in

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vitro as well as in vivo models, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of revefenacin is predominantly a site-specific effect.

DOSAGE AND ADMINISTRATION

The recommended dosage is 175 mcg YUPELRI (one 175 mcg unit-dose vial) administered by oral inhalation once daily by nebulizer using a mouthpiece.

Administration Overview

YUPELRI should be administered by the orally inhaled route via a standard jet nebulizer

connected to an air compressor. The safety and efficacy of YUPELRI have been established in clinical trials when administered using the PARI LC® Sprint nebulizer with a mouthpiece and the PARI Trek® S compressor. The safety and efficacy of YUPELRI delivered from non-compressor based nebulizer systems have not been established.

The YUPELRI unit-dose vial should only be removed from the foil pouch and opened IMMEDIATELY BEFORE USE. The vial and any residual content should be discarded after use.

No dosage adjustment is required for geriatric patients, or patients with renal impairment

The drug compatibility (physical and chemical), efficacy, and safety of YUPELRI when mixed with other drugs in a nebulizer have not been established.

CONTRAINDICATIONS

YUPELRI is contraindicated in patients with hypersensitivity to revefenacin or any component of this product.

WARNINGS AND PRECAUTIONS

Deterioration of Disease and Acute Episodes: YUPELRI should not be initiated in patients during acutely deteriorating or potentially lifethreatening episodes of COPD. YUPELRI has not been studied in subjects with acutely deteriorating COPD. The initiation of YUPELRI in this setting is not appropriate.

YUPELRI is intended as a once-daily maintenance treatment for COPD and should not be used for relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm, and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

Paradoxical Bronchospasm: As with other inhaled medicines, YUPELRI can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs following dosing with YUPELRI, it should be treated immediately with an inhaled, short-acting bronchodilator; YUPELRI should be discontinued immediately and alternative therapy should be instituted.

Worsening of Narrow-Angle Glaucoma: YUPELRI should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g. eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately if any of these signs or symptoms develops.

Worsening of Urinary Retention: YUPELRI should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g. difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of YUPELRI. If such a reaction occurs, therapy with YUPELRI should be stopped at once and alternative treatments should be considered.

DRUG INTERACTIONS

Anticholinergics

There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of YUPELRI with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Transporter-Related Drug Interactions: OATP1B1 and OATP1B3 inhibitors (e.g. rifampicin, cyclosporine, etc.) could lead to an increase in systemic exposure of the active metabolite. Therefore, coadministration with YUPELRI is not recommended.

USE IN SPECIFIC POPULATIONS

Pregnancy: There are no adequate and well-controlled studies with YUPELRI in pregnant women. Women should be advised to contact their physician if they become pregnant while taking YUPELRI. In animal reproduction studies, subcutaneous administration of revefenacin to pregnant rats and rabbits during the period of organogenesis produced no evidence of fetal harm at respective exposures approximately 209 times the exposure at the maximum recommended human dose (MRHD) (on an area under the curve [AUC] basis).

Lactation: There is no information regarding the presence of revefenacin in human milk, the effects on the breastfed infant, or the effects on milk production. However, revefenacin was present in the milk of lactating rats following dosing during pregnancy and lactation.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for YUPELRI and any potential adverse effects on the breastfed infant from YUPELRI or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of YUPELRI have not been established in pediatric patients.

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YUPELRI is not indicated for use in children.

Hepatic Impairment: The systemic exposure of revefenacin is unchanged while that of its active metabolite is increased in subjects with moderate hepatic impairment. The safety of YUPELRI has not been evaluated in COPD patients with mild-to-severe hepatic impairment. YUPELRI is not recommended in patients with any degree of hepatic impairment.

Renal Impairment: No dosage adjustment is required in patients with renal impairment. Monitor for systemic antimuscarinic side effects in COPD patients with severe renal impairment.

OVERDOSAGE

An overdosage of YUPELRI may lead to anticholinergic signs and symptoms such as nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure (causing pain, vision disturbances, or reddening of the eye), obstipation or difficulties in voiding.

Treatment of overdosage consists of discontinuation of YUPELRI along with institution of appropriate symptomatic and/or supportive therapy.

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